HIV reveals site of vulnerability

Medical researchers have found a chink in the constantly shape-shifting armour of the HIV virus. The discovery could be a
significant step forward in the ongoing quest for a vaccine.

The AIDS virus evades the immune system because most of the proteins that cover the surface of the virus constantly change
their structure. But researchers have now identified a site that doesn't change, and shown how an antibody can bind to it.
If the body could be stimulated to produce its own copies of this antibody before infection, then in theory, it would allow
it to attack the otherwise elusive virus and prevent infection.

"For a long time people have been asking whether an HIV vaccine is even possible," says Peter Kwong of the US National Institute
of Allergy and Infectious Diseases in Bethesda, Maryland, who led the research. "What this finding says is that it's not just
a dream — there is this site of vulnerability."

Hide and seek

The discovery hinges on an HIV protein called gp120. During infection, gp120 latches onto a protein found in the human immune
system called CD4. Because this is an essential step in the virus's replication cycle, a key site within gp120 retains its
conformation, unlike other HIV surface proteins.

Vaccine researchers have known about this process for years, but there was a stumbling block. Previously, they thought that
this site for antibody binding was hidden within the folds of the gp120 protein until the crucial moment of infection. This
masking would mean that antibodies would not be able to recognize the unchanging portion and bind to it.

But Kwong and his colleagues have now shown that is not the case. This key part of gp120 are never hidden, they found — the
protein doesn't change shape until after gp120 binds with CD4. This means that the never-changing binding site is not locked
away from antibodies after all.

What's more, the team has succeeded in getting an antibody, called b12, to bind to gp120, and has studied the process to reveal
the structure of the two molecules as they clamp together. They report their discovery in Nature1.

Mass production

The b12 antibody is already known to protect monkeys from infection with the related simian immunodeficiency virus. The challenge
now lies in finding a way to get the human body to produce lots of b12 antibodies.

A vaccine could do this in several ways, says Kwong. It could be a protein or a string of DNA that gives the body information
on how to produce b12. Or a part of the HIV gp120 protein could be used to stimulate the body to raise antibodies against
it.

Some people infected with HIV have developed similar antibodies. But because they have already been exposed to the virus,
it is too late to prevent permanent infection. So, such a vaccine would work only if given before infection.

The question, says Kwong, is whether a drug can be developed that stimulates antibody production in someone who has never
encountered the virus. The researchers now plan animal tests to see whether high levels of the antibody can be achieved.